A phase 1 dose-escalation study of irinotecan in combination with 17-allylamino-17-demethoxygeldanamycin in patients with solid tumors.
OBJECTIVE
Both heat shock protein 90 (Hsp90) and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors.


METHODS
During the dose escalation phase, patients received i.v. irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity.


RESULTS
Twenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity at dose level 4 (100 mg/m(2) irinotecan and 375 mg/m(2) 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by the coadministration of irinotecan, and vice versa. There was no partial response, although tumor shrinkage was observed in six patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P = 0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G(2)-M cell cycle checkpoint, and cell death could be shown in tumor biopsy samples obtained at the MTD.


CONCLUSIONS
The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m(2) irinotecan and 300 mg/m(2) 17AAG.
Tse
Archie N
AN
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. tsea@mskcc.org
Klimstra
David S
DS
Gonen
Mithat
M
Shah
Manish
M
Sheikh
Tahir
T
Sikorski
Rachel
R
Carvajal
Richard
R
Mui
Janet
J
Tipian
Caroll
C
O'Reilly
Eileen
E
Chung
Ki
K
Maki
Robert
R
Lefkowitz
Robert
R
Brown
Karen
K
Manova-Todorova
Katia
K
Wu
Nian
N
Egorin
Merrill J
MJ
Kelsen
David
D
Schwartz
Gary K
GK
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016227:Benzoquinones / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D000077146:Irinotecan; D047029:Lactams, Macrocyclic / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D000077146:Irinotecan; D002166:Camptothecin